Project Summary/Abstract The personal, societal, and economic burden that disorders of the central nervous system (CNS) place on the United States is tremendous. From 2003-2014, the FDA approved just 37 new drugs to treat CNS disorders covering the clinical areas of neurology, psychiatry, and pain. That averages to just three new chemical entities (NEIs) per year, while clinical trial failure rates for CNS drug development remain greater than 90%. Although the reasons for this exceedingly high level of attrition are myriad and complex, the central challenge to drug development is that platforms for early preclinical identification and validation of novel compounds are often not relevant to the disease target cells and phenotypes. BrainXell, Inc. seeks to address these issues head-on by generating in vitro model systems with human neurons and astrocytes that more closely approximate the human CNS. Functional loss or impairment of astrocytes is implicated in a wide range of pathological processes and neural disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and epilepsy. This SBIR Phase I proposal is to produce large quantities of highly enriched, regional specific astrocytes in a rapid and consistent manner that meet high-throughput screening (HTS) requirements. Recently, we have developed a novel method for rapid generation of enriched and functional spinal astrocytes from iPSCs in 4 weeks by applying inducible expression of gliogenic transcription factors NFIA and SOX9. In this study, we will apply the same strategy to generate other regional specific astrocytes, such as cortical, midbrain, and hindbrain astrocytes as well as ALS disease astrocytes. We will then validate whether these astrocytes produced in vitro can exhibit similar gene expression and function as their in vivo and disease counterparts. The success of this study will not only enable us to expand our astrocyte product line, but also provide a service to manufacture astrocytes from patient iPSCs for drug discovery.